Monopolar spindle 1 (Mps1/TTK) kinase is a key component of the spindle assembly checkpoint (SAC), which is essential for cell survival. CFI-402257 is orally bioavailable, highly selective inhibitor of Mps1 with an IC50 value of 1.2 ± 0.4 nM and is ATP competitive with a Ki value of 0.09 ± 0.02 nM. In cells exogenously expressing human Mps1, CFI-402257 blocked auto-phosphorylation of Mps1 at threonine 12/serine 15 with an EC50 value of 6.5 ± 0.5 nM. CFI-402257 also exerts inhibitory activity on the activation of the SAC with an IC50 value of 64 ± 5 nM. Treatment of HCT116 cells with 200 nM CFI-402257 led to a remarkable increase in chromosome missegregations compared to DMSO-treated control cells. CFI-402257 at 50 - 3000 nM increased the frequency of HCT116 cells with an aneuploid DNA content, and the massive aneuploidy was observed when cells were dosed with 100 nM CFI-402257. Moreover, CFI-402257 exhibited potent growth inhibitory effect on a vast majority of human cancer cell lines with a median IC50 value of 15 nM. In a mouse xenografted model of MDA-MB-231 human TNBC cells, daily oral administration of CFI-402257 at 5 mg/kg and 6 mg/kg for 22 days showed tumor growth inhibition (TGI) of 74% and 89%, respectively. Similar results were found in mice xenografted with MDA-MB-468 human TNBC cells (5 mg/kg, TGI = 75%; 6 mg/kg, TGI = 94%). In addition, significantly decreased number of phospho-histone H3 serine 10-positive cells per square millimeter of tumor tissue was observed in CFI-402257-treated tumors (6 mg/kg and 35 mg/kg) as compared to vehicle controls[3].
CFI-402257 细胞实验
Cell Line
Concentration
Treated Time
Description
References
Normal mesothelial cells
20-40 nM
5 days
CFI-402257 had no significant effect on normal mesothelial cells at the same concentrations.
Oncogene. 2017 Nov 16;36(46):6501-6507.
U87 cells
1 μM
48 hours
To evaluate the effect of CFI-402257 on the proliferation of U87 cells, results showed that CFI-402257 significantly inhibited the proliferation of U87 cells.
BMC Cancer. 2022 Jul 18;22(1):786.
U251 cells
0.5 μM
48 hours
To evaluate the effect of CFI-402257 on the proliferation of U251 cells, results showed that CFI-402257 significantly inhibited the proliferation of U251 cells.
BMC Cancer. 2022 Jul 18;22(1):786.
RB1-deficient ER+ breast cancer cell lines
150 nM
72 hours
To assess the impact of RB1 loss on sensitivity to CFI-402257, results showed that RB1-deficient cells were more sensitive to CFI-402257, inducing higher levels of apoptosis
Sci Adv. 2022 Sep 9;8(36):eabq4293.
ER+ breast cancer cell lines
150 nM
48 hours
To evaluate the sensitivity of CDK4/6i-resistant cells to CFI-402257, results showed that CFI-402257 induced premature chromosome segregation, increased DNA damage, and cell death
Proc Natl Acad Sci U S A. 2022 Aug 9;119(32):e2119514119.
HCT116 cells
100 nM
2 days
CFI-402257 induced aneuploidy, accompanied by accumulation of apoptotic cells
Proc Natl Acad Sci U S A. 2017 Mar 21;114(12):3127-3132.
HCT116 cells
200 nM
2 hours
CFI-402257 caused chromosome missegregation, increasing the percentage of lagging chromosomes
Proc Natl Acad Sci U S A. 2017 Mar 21;114(12):3127-3132.
MDA-MB-436
150 nM
72 hours
induced apoptosis and potentiated aneuploidy
Proc Natl Acad Sci U S A. 2018 Feb 13;115(7):E1570-E1577.
MDA-MB-468
150 nM
72 hours
induced apoptosis and potentiated aneuploidy
Proc Natl Acad Sci U S A. 2018 Feb 13;115(7):E1570-E1577.
MDA-MB-231
150 nM
72 hours
induced apoptosis and potentiated aneuploidy
Proc Natl Acad Sci U S A. 2018 Feb 13;115(7):E1570-E1577.
MCF-7 cells
0-1000 nM
72 hours
Evaluate the cytotoxicity of CFI-402257, results showed lower toxicity in MCF-7 cells
Oncol Rep. 2024 Aug;52(2):101.
HMEC cells
0-1000 nM
72 hours
Evaluate the cytotoxicity of CFI-402257, results showed lower toxicity in HMEC cells
Oncol Rep. 2024 Aug;52(2):101.
MDA-MB-231 cells
0-1000 nM
72 hours
Evaluate the cytotoxicity of CFI-402257, results showed CFI-402257 selectively induced cytotoxicity in MDA-MB-231 TNBC cells
Oncol Rep. 2024 Aug;52(2):101.
Malignant mesothelioma cell lines
100 nM
30 minutes to 72 hours
CFI-402257-mediated inhibition of Mps-1 resulted in abrogation of the mitotic checkpoint, premature progression through mitosis, marked aneuploidy and mitotic catastrophe.
Oncogene. 2017 Nov 16;36(46):6501-6507.
CFI-402257 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
BALB/c mice
Orthotopic, syngeneic model of malignant mesothelioma
Oral gavage
7 mg/kg
Daily, till study end-point
CFI-402257 significantly reduced tumor growth as a single agent and showed enhanced effect when combined with cisplatin+pemetrexed.
Oncogene. 2017 Nov 16;36(46):6501-6507.
Mice
Carotid artery wire injury model and HFD-fed ApoE−/− mice
Oral
1, 2, or 4 mg/kg body weight
Once daily for 28 days (wire injury model) or 12 weeks (atherosclerosis model)
To evaluate the effect of CFI-402257 on postinjury neointimal formation and atherosclerosis, results showed it significantly inhibited neointimal formation and atherosclerotic plaque area without impairing reendothelialization
Adv Sci (Weinh). 2025 Feb;12(6):e2409250.
SCID mice
MCF7 RB1-deficient xenograft model
Oral administration
6 mg/kg (daily) and 25 mg/kg (2 days on/5 days off)
Daily or 2 days on/5 days off, for up to 38 days
To evaluate the antitumor activity of CFI-402257 in RB1-deficient tumors, results showed that CFI-402257 significantly inhibited tumor growth
Sci Adv. 2022 Sep 9;8(36):eabq4293.
SCID beige mice
TCL xenograft model
Oral
6 mg/kg/day
Once daily for one week
Inhibited tumor growth, reduced tumor volume and weight
Adv Sci (Weinh). 2025 Mar;12(10):e2413990.
BALB/cAnN-nu mice
HCC model
Oral
6 mg/kg/day
Once daily for 19 days
Assessed the inhibitory effect of CFI-402257 on HCC growth
Proc Natl Acad Sci U S A. 2022 Aug 9;119(32):e2119514119.
Mice
MDA-MB-231 human TNBC xenograft model
Oral
6 mg/kg
Once daily for 22 days
CFI-402257 significantly inhibited tumor growth with a TGI of 89%
Proc Natl Acad Sci U S A. 2017 Mar 21;114(12):3127-3132.
BALB/c nude mice
MDA-MB-231 xenograft model
Oral and intraperitoneal injection
1 mg/kg
Once daily for 28 days
Evaluate the antitumor effect of CFI-402257 and AICAR combination therapy, results showed significant tumor growth inhibition
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